Schizophrenia is a debilitating illness that affects up to 1% of the world's population. While the use of antipsychotic (neuroleptic) drugs is the standard of care for treating the psychotic symptoms of the illness, little is known regarding which neuroleptics are best for extended use in those with cognitive impairment. This consistent feature of schizophrenia is now believed to have the most substantial impact on the longterm outcome of the disease. Accordingly, a major long-term goal of this laboratory is to develop mechanistically-based therapeutic strategies for patients suffering from psychotic symptoms and cognitive dysfunction. The objective of this application is to establish potential relationships between the cellular and biochemical effects of chronic neuroleptic exposure and cognitive function in an experimental animal model. We have compelling preliminary evidence from rat studies that chronic exposure to conventional neuroleptics such as haloperidol (in a temporally dependent fashion), but not atypical agents such as clozapine, leads to cognitive impairment and that a reduction in a key marker for cholinergic neurons, choline acetyltransferase, precedes the cognitive symptoms. Due to the pattern of reduced cholinergic enzyme staining and the fact that many of the cholinergic neurons involved in learning and memory are functionally dependent on the neurotrophin, nerve growth factor (NGF), we have developed the hypothesis that chronic exposure to conventional, but not atypical, neuroleptics in rats decreases neurotrophic support to cholinergic neurons, resulting in decreased cholinergic activity in the brain and impairment of cognitive function. The rationale for the proposed animal studies is that a better understanding of the differential (chronic) effects of neuroleptics on memory function will facilitate future (clinical) efforts to identify optimal drugs for cognitively impaired psychiatric patients. To test the hypothesis we propose two specific aims: 1): To evaluate differential temporal effects of different classes of neuroleptic drugs on cognitive function in an experimental animal model. 2): To define potential correlative relationships between neuroleptic-induced cognitive changes and temporal changes in biochemical and cellular parameters of cholinergic function in the brain, NGF release, and NGF receptor expression. We will use a water maze task to measure spatial learning, an 8-arm radial arm maze task to assess working memory, and in situ hybridization, western blots, ELISA experiments, immunofluorescence staining, and receptor autoradiography to measure the expression of NGF and key cholinergic markers. We expect that chronic exposure to conventional, but not atypical neuroleptics will negatively affect both spatial learning and working memory and that neuroleptic-induced alterations in CNS cholinergic activity will both precede and correlate with detectable manifestations of cognitive dysfunction. These studies, designed to mechanistically define neuroleptics based on their chronic effects on specific biological substrates of memory are significant because they will contribute to the identification of therapeutic agents with optimal effects on cognitive function, and thus potentially benefit many psychiatric patients. [unreadable] [unreadable]